The interest for monolithic devices for the controlled release of drugs is continuously growing, and much effort has been done for the development of novel pharmaceutical dosage forms ensuring more constant release rate of liberation over extended periods of time.
Various polymers, such as vinylic polymers, polyethylene, silicone, ethylcellulose, acyl-substituted cellulose, poly(hydroxyethylmethacrylate)-PHEMA, acrylic copolymers and the like, have been proposed for use as matrices for drug controlled release, (see for example U.S. Pat. No. 3,087,860, U.S. Pat. No. 2,987,445, U.S. Pat. No. 4,761,289 and Pharm. Acta Helv., 1980, 55, 174-182, Salomon et al.). Despite the multitude of these polymeric matrices that have been developed (hydrogels, hydrophillic, hydrophobic and the like), no ideal matrix conferring a sustained drug release at a constant rate is known. In this context, many physical and chemical systems have been suggested, most of them based on diffusion-controlled, swelling-controlled or chemically-controlled (external bioerosion) drug release.
The diffusion controlled systems, which require hydrophillic polymers such as hydroxyethylcellulose, sodium-carboxymethylcellulose and the like, allow a sustained release of drugs, but do not permit a rigorous control since the release rate is not constant.
The swelling-controlled systems are based on glassy homogeneous polymeric matrices free of internal channels, into which the water front penetrates at a constant rate. Behind this front, the polymer is in a rubbery state. If the diffusion coefficient of the drug is significantly higher in the rubbery state than in the glassy state of the polymer, a zero order release can be obtained, but only for a limited degree of release, usually around 60% from the total amount of loaded drug, and this only for the case of relatively low initial drug concentration (see N. Peppas and N. Franson, J. Polym. Sci., 21, 983-997, 1983. Another mechanism allows a slow drug release mediated by the tablet external bioerosion during its gastroenteric residence (E. Doelker and P.Buri, Pharm. Acta Helv., 56, 111-117, 1981). This system is mainly based on starch or lipidic matrices, and the rate of drug release is related to the complex composition of the gastric fluids (including its enzymatic set) and is therefore susceptible to variations from one individual to another.
Although these mechanisms allow interesting release kinetics, the release times and the linearity of the dissolution curves, are still to be improved.
Cross-linked amylose (CLA), a semisynthetic material obtained by the cross-linking of amylose with a cross-linking agent such as epichlorohydrin or 2,3-dibromopropanol, has recently been introduced as a matrix for drug controlled slow release, wherein the drug dissolution rate is controlled by a mechanism based on hydrogen associations established following the compression, between amylose chains (see U.S. Ser. No. 787,721 filed Oct. 31, 1991). Such CLA matrix provides substantially linear release kinetics.
However, the release times of certain drugs, mainly the ones with a limited aqueous solubility or presenting some affinity interactions with the CLA matrix, can sometimes be higher than the usual release time observed for the majority of pharmaceutical products, which is about 15-24 hours. Release times exceeding 24 hours are generally undesirable, except for rare occasions. Furthermore, there are several drugs (cardiovascular, anaesthetics, sedatives, antihistaminics, etc.) for which the optimal release time is of 6-12 h.
It would therefore be highly desirable to obtain a slow release pharmaceutical dosage unit which would permit a controlled slow release of the drug present therein. Such pharmaceutical dosage unit would further allow the control of the time of release depending on the optimal time required for a given pharmaceutical product.